3-Benzylpyrido {8 3,4-e{9 -as-triazine and 1,2-dihydro-3-benzylpyrido{8 3,4-e{9 -as-triazine hydrochloride

ABSTRACT

The titled compounds are effective antifungal agents adapted to be combined in pharmaceutical forms for use in the eradication of fungus infections.

United States Patent [1 1 Wright et a].

1 May 13, 1975 3-BENZYLPYRIDO [3,4-El-AS-TRIAZINE AND l,2-DIHYDRO-Ii-BENZYLPYRIDO[3,4-E1- AS-TRIAZINE HYDROCHLORIDE [75] Inventors: George C. Wright; Allan V. Bayless;

Joseph E. Gray, all of Norwich,

[73] Assignee: Morton-Norwich Products, Inc., Norwich, NY.

[22] Filed: June 6, 1973 [21] Appl. No.: 367,500

[52] [1.5. CI. 260/248 AS; 424/249 [5 l] Int. Cl C07d 57/34 Primary Examiner-John M. Ford Attorney, Agent, or Firm-Anthony J. Franze [57] ABSTRACT The titled compounds are effective antifungal agents adapted to be combined in pharmaceutical forms for use in the eradication of fungus infections.

3 Claims, No Drawings 1 3-BENZYLPYRIDO [3,4-E]-AS-TRIAZINE AND 1,2-DIHYDRO-3-BENZYLPYRIDO[3,4-E1-AS- TRIAZINE HYDROCHLORIDE This invention is concerned with the chemical compounds 3-benzylpyrido[3,4-el-as-triazine and 1.2- dihydro-3-benzy1pyrido(3,4-el-as-triazine hydrochloride. These compounds are effective antifungal agents. They are readily prepared in accordance with the following examples:

EXAMPLE I 1,2-Dihydro-3-benzylpyrido[ 3,4-e1-as-triazine drochloride A. Ethyl 3-( 3-nitro-4-pyridy1)carbazate Hydrochloride To a solution of 91 g (0.57 mole) of 4-chloro-3- nitropyridine in 600 ml. of phenol was added 62 g (0.60 mole) of ethyl carbazate at 4050, using mechanical stirring. The reaction was exothermic over ca 5 min, with a temperature rise to 72. The reaction solution was heated on the steam bath for 1% hr, cooled to 3540, and added to 3.2 1 of anhydrous ether. After standing at room temperature for ca min, the supernatant solution was decanted, and the resultant amor phous solid was washed twice with anhydrous ether. The solid was treated with 500 ml of isopropanol, heat ing on the steam bath with trituration, affording a light yellow, crystalline solid. Upon cooling in an ice bath for ca 10 min, the initial product was collected, washed well with isopropanol and ether, and dried in a vacuum dessicator overnight. Yield: 55 g (37 percent). The product was recrystallized from 700 ml of ethanol, m.p. 203-204. Yield: 40 g.

Anal: Calcd. for C H, N,O .HC]: C, 36.58; H, .22; N, 21.33. Found: C. 36.70; H, 4.22; N, 21.65.

B. 4-l-lydrazino-3-nitropyridine Hydrochloride A solution of 87 g (0.33 mole of A. in 520 ml. of concentrated HCl was heated to dryness over 23 hr on a steam bath. The yellow residue was slurried in 200 ml of ethanol, refluxed for 20 min, and filtered hot. The red crystalline solid was washed with 100 ml of isopropanol, 200 ml of ether, and dried, m.p. 2 l922l dec. Yield: 39 g (56 percent).

The crude product was recrystallized from 1050 ml of methanol, washed with five 20-m1 portions of methanol, 250 ml of ether, and dried; m.p. 225-227 dec. Yield: 24 g (38%|.

Anal. Calcd. for C:,H N.,O .HCl: C, 31.51; H, 3.70; N, 29.40; Cl, 18.60. Found: C, 31.60; H, 3.80; N, 29.66; C1, 1850.

C. 3-Amino-4-hydrazinopyridine Hydrochloride A 22 g (0.12 mole) portion of B. was slurried in 170 ml of ethanol, treated with 1.4 g of 5% Pd/C (50 percent moisture) and subjected to hydrogenation at 50 psig. The hydrogen uptake was 30 lbs in 4 hrs. The reduction mixture was cooled for 2 hrs and filtered. The product plus catalyst was washed with three 2 lO-rnl portions of isopropanol, ether, and dried, m.p. 2l7-2l8 decompn. Yield: 17 g (92%).

This procedure was repeated more to give a combined total of 34 g of the product plus catalyst. The crude product, 34 g, was recrystallized from 1.7 1 of methanolzl-QO (19:1), washed with 170 ml of methanol, 300 ml of ether and dried, m.p. 223-225 decompn. Yield: 23 g (61 percent).

Anal. Calcd. for C .,H,,N,.HC1: C, 37.39; H, 5.65; N, 34.89. Found: C, 37.14; H, 5.58; N. 34.72.

D. 1,2-Dihydro-3-benzylpyrido[3,4-e]-as-triazine Hydrochloride A mixture of 35.4 g (.22 mole) of C. and 60 g (.44 mole) of phenyl-acetic acid was heated in a 130-135 bath for 2 hrs. It was then cooled and shaken with a mixture of 350 ml of chloroform and 400 ml of water. The water layer was washed with three 300 ml portions of chloroform and evaporated to dryness under vacuum. The resulting red oil was dissolved in 400 ml of absolute ethanol. A precipitate formed which was filtered and washed with ethanol and then ether. Yield: 30 g, m.p. 268270 (decomposes). This was recrystallized from anhydrous methanol to yield m.p. 265-275 (decomposes).

Anal. Calcd. for C, H, N,.HCl: C. 59.88; H, 5.03; N, 21.49.

Found: C, 59.77; H, 4.96; N, 21.57.

EXAMPLE ll 3-Benzylpyrido[3,4-3l-as-triazine To a solution of 20 g (.077 mole) of the compound of Example 1 in 400 ml of water and ml of ethanol was added to a solution of 6.5 g (.077 mole) of NaH- CO in 50 m1 of water. Manganese dioxide (60 g) was added and the reaction was stirred for 1% hr. The reaction was filtered and the residue was washed with chloroform until the washings were colorless (300 ml). The chloroform layer was washed with water, filtered through anhydrous MgSO. and flash-evaporated to dryness. Yield: 16 g (94%), m.p. 76-78.5.

Anal. Calcd. for C H N C, 70.25; H, 4.54, N, I

Found: C, 70.20; H, 4.53; N,

The compounds of this invention are potent antifungal agents. They are capable in small concentration of inhibiting the growth of pathogenic fungi such as Candida albicans and Microsporum Cam's, Such capabilities are represented in the table herebelow which reflects results secured in the commonly used in vitro antifungal test employing Sabourauds dextrose agar as the medium supportive of fungal growth and measuring the amount of inhibition of such growth in millimeters over a period of eight days:

Diameter of Zone of Inhibition in mm at Days Cone.

in C ulbimns M r (unis Compound mcglml 2 4 6 8 4 6 8 Example I 2000 35 33 32 3i I 52 52 52 Example ll I860 33 33 33 32 l8 10 ll) 'Thc diluent carrier for the compound in this test is 50; ethanol which exhibits no antifungal activity A noteworthy characteristic of the compounds of this invention is their lack of irritation to the skin. When applied daily in the form of a suspension at concentra tions up to 4 percent in a vehicle of aqueous methyl cellulose, no skin irritation was observed over a period of manganese dioxide. 

1. THE COMPOUND 1,2-DIHYDRO-3-BENZYLPYRIDO-(3,4-E)-ASTRIAZINE HYDROCHLORIDE.
 2. The compound 3-benzylpyrido(3,4-e)-as-triazine.
 3. The method of preparing 3-benzylpyrido(3,4-e)-as-triazine which consists in oxidizing 1,2-dihydro-3-benzylpyrido(3,4-e)-as-triazine hydrochloride with manganese dioxide. 